Hepatitis B virus (HBV) is clearly associated with hepatocellular carcinomas, yet the mechanism of carcinogenesis is poorly understood. One possibility, strengthened by recent transgenic mouse studies, is that cellular necrosis and regeneration contribute significantly to carcinogenesis. In chronic HBV infection, there is appearance of so-called ground glass cells, which are cells with inspissated HBV surface proteins in the endoplasmic reticulum. Ground glass cells in transgenic mice can cause sufficient cellular damage and hepatic regeneration to induce hepatocellular carcinomas. Therefore, we would like to investigate how ground glass cells are produced in human infections. Our hypothesis is that genomic rearrangements of the HBV DNA, almost invariably present during chronic infection, cause dys-regulated transcription of the viral surface gene. This, in turn, leads to over synthesis of the large form of the surface protein, which is known to be capable of causing ground glass cells. We will test our hypothesis by generating mutant HBV clones, and looking for surface gene dys-regulation by transient transfections. We will further confirm that these mutations can cause ground glass cells in cultured cells and transgenic mice. It is hoped that these studies will lead to new insights on the pathogenesis of ground glass cells, and ultimately of hepatocellular carcinoma in HBV infection.